Muscle movement is a very prevalent and daily task all humans utilize, but what if our muscles just stopped working, or never worked to begin with? This is a characteristic of Pompe disease, an inherited disorder caused by a buildup of complex sugar, glycogen, in the body’s cells. This is an autosomal recessive disorder, so even if prospective parents don’t have symptoms of the disease, they could be carrying genes that could be passed on to future offspring. Three types of Pompe disease can occur if the offspring has both recessive alleles contributing to the GAA gene but are found at different stages in life. The first is the Classic Infantile-Onset, beginning within a few months of birth. These babies experience muscle weakness, poor muscle tone, heart and liver defects and may experience failure to thrive. If untreated, this can lead to death within the first year. The second type is introduced around the first year of a child’s life, with similar symptoms to infantile-onset, but these children usually only live into early childhood. Lastly, late-onset is apparent later in childhood, adolescence or adulthood. These symptoms are usually milder and less likely to involve the heart, but do experience muscle weakness, usually in the muscles which control the lungs, leading to respiratory failure. Pompe disease occurs due to the deficiency of the enzyme Alpha Acid-Glucosidase (GAA), which is responsible for hydrolyzing lysosomal glycogen. Due to the lack of GAA, lysosomal glycogen accumulates in many tissues with skeletal, cardiac and smooth muscle. This leads to progressive debilitation, organ failure, and death. There have been more than 200 mutations in the GAA gene described up to date. Incidence reports range from 1 in 14",000 to 1 in 300",000 depending upon ethnicity or the demographic studied. It has been seen that Infantile-Onset has a higher prevalence among African-Americans and Chinese whereas the late-onset adult form has a higher incidence in The Netherlands. The combined incidence reports are estimated to be 1:40",000. There are some populations in which particular mutations are more common due to founder effects while allelic heterogeneity can be significant in admixed populations in the United States. With the disease being very fast acting, specifically in Infantile-Onset, early recognition should be a priority. Enzyme Replacement Treatment (ERT) is now available using alglucosidase alpha and has been associated with an improved response. ERT in infants resulted in a reduced risk of invasive ventilation and of any type of ventilation, and treatment prior to 6 months of age have shown better outcomes compared to later treatments. Without ERT in Infantile-Onset, the disease is fatal within the first year of life in majority of the cases.
Assessment of Pompe Disease can be done through multiple tests, indicating the deficiency of GAA enzyme. Two types of genetic testing can attribute to carrier detection, biochemical testing and molecular testing. The biochemical approach is the gold standard; measuring GAA activity is in skin fibroblasts, obtained from a skin biopsy, muscle biopsy, purified lymphocytes, mononuclear cells and lymphoid cell lines. This shows the presence of vacuoles that stain positively for glycogen, which has been accumulated in the lysosomes and dispersed in the cytosol. This is not the most reliable for carrier determination because of significant overlap in residual enzyme activity levels between obligate carriers and non-carriers. As well, using Dried Blood Spot (DBS) investigation can be done to measure GAA activity in newborns. For Later-Onset diagnosis, adults should be referred to a pulmonologist for regular evaluation to delay mechanical ventilation. To identify carriers, mutation analysis is the only way to do so. There have been advances in technology to test for several muscle disorders, called next-generation sequencing. A gene panel is designed to analyze the coding sequences and splice site junctions of GAA causing muscle weakness from different disorders with overlapping phenotypes. Due to potential overlap of residual GAA enzyme activity with heterozygotes in late-onset, molecular analysis of the GAA gene may be required to confirm the diagnosis.
Stated previously, Pompe disease can lead to death within the first year of a child’s life, causing the utmost dismay and pain in prospective parents’ lives. Genetic testing can allow parents to potentially prevent or cause awareness for potential risks or mutations that can be passed on as they procreate. Even in adults, many Late-Onset causes lead to death at a step-wise pace, which can be prevented and watched for throughout the patient’s life. If genetic testing is not done prior to pregnancy, a test should be done within the first 6 months of a child’s life to access preventative measures and hopefully save a life.